A team of scientists at the National Institutes of Health (NIH) has identified a gene that can cause multiple benign tumors of the parathyroid and pituitary glands, as well as islet cell tumors leading to pancreatic cancer. Their discovery of the gene for multiple endocrine neoplasia, type 1 (MEN1), is reported in the April 18 issue of the journal
Science.

As a result of the discovery, doctors will soon be able to screen families at risk for MEN1 more easily and eliminate periodic blood tests for those with normal MEN1 genes. They hope to learn from MEN1 and its protein product, called menin, how endocrine tumors and cancers grow. The discovery also provides a target for the design of drugs to prevent or treat both benign and malignant endocrine tumors.

The MEN1 gene, a tumor suppressor gene--a gene that inhibits abnormal cell growth--intrigues researchers because it is unlike any of the tumor suppressors currently known, according toAllen Spiegel, M.D., scientific director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which initiated the work.

"Its broad function is to inhibit cell growth, somehow," adds senior investigator Stephen J. Marx, M.D., also of NIDDK, "but in fact, it is unlike any human protein we have seen. It's a real black box."

Drs. Marx and Spiegel collaborated with Francis Collins, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI) and Settara C. Chandrasekharappa, Ph.D., also of NHGRI, and Lance Liotta, M.D., Ph.D., and Michael Emmert-Buck , M.D., Ph.D., of the National Cancer Institute (NCI) to find and capture the gene.

"This gene could indicate the presence of an entirely new pathway for the control of cell growth," says Dr. Collins.

MEN1 is expressed throughout the body, not just in the endocrine glands as scientists might have predicted based on the endocrine tumors characteristic of the disease. The researchers say they wouldn't be surprised if mutations of MEN1 also contribute to the growth of other more common, nonhereditary endocrine tumors, as well as to the growth of unexpected cancers. There is, for example, an unknown gene implicated in some forms of breast cancer also located at 11q13, which NCI researchers plan to explore,
according to Dr. Liotta.

A tumor suppressor gene acts like a set of brakes on abnormal cell growth. When a mutation in the gene occurs, the brakes are lost and cells multiply. A person inherits two copies of a tumor suppressor gene, one from each parent. A parent who has MEN1 or some other inherited cancer syndrome passes on a malfunctioning tumor suppressor gene,
leaving a child with only one normal copy of the gene. If that single, normal gene mutates because of environmental or other random influences, all the brakes are gone and that cell can grow out of control, forming a tumor.

That is what happens in MEN1, an inherited endocrine disorder that causes simultaneous, multiple tumors of the parathyroid and pituitary glands and of islet cells in the pancreas. Parathyroid and pituitary tumors are almost always benign, but abnormal hormone secretion by these tumors is an important cause of disease.

Parathyroid tumors, for example, lead to primary hyperparathyroidism (HPT), with high blood calcium, which is one of the first signs of MEN1. HPT can cause weakened bones, pain, fatigue, and kidney stones; when associated with MEN1, HPT is more difficult to cure because all the parathyroid glands are affected by multiple tumors.

Another consequence of MEN1 may be too much gastrin in blood, which causes severe stomach ulcers that are sometimes fatal. Some islet cell tumors may become malignant and result in a lethal form of pancreatic cancer.

The discovery of the gene emanated from the unique collaboration of four different research teams at the NIH and a team at the University of Oklahoma.

NIDDK scientists Drs. Stephen Marx and Allen Spiegel and colleagues have been treating and studying patients with MEN1 at the NIH Clinical Center for more than 20 years. They accumulated 65 families with MEN1, collecting blood and tumor tissue samples from which they isolated DNA.

In 1994, the NHGRI researchers began collaborating with NIDDK to search for the MEN1 gene. NHGRI scientists used a powerful gene-hunting technique called positional cloning that involved assembling nearly 3 million base pairs of continuous DNA in small fragments to identify new markers and genes that were candidates for MEN1.

Drs. Liotta and Emmert-Buck and colleagues of NCI's laboratory of pathology joined the collaboration to study tumors from MEN1 patients in order to help identify the gene. In 1996, Drs. Liotta and Emmert-Buck and colleagues developed tissue microdissection, the latest version of which uses a single-shot laser beam to remove a tumor cell from surrounding normal tissue under a microscope. With this technique, the scientists were able to search tumor tissue for loss of a segment of the normal copy of the chromosome a patient would have inherited from an unaffected parent, and to identify a specific region that might harbor the sought-after gene. "We were able to look at the tissue sample and say 'Here's the DNA segment to search'," says Dr. Emmert-Buck of NCI. Scientists could then analyze the DNA.

Drs. Collins and Chandrasekharappa began the arduous task of cloning and sequencing the chromosome region. Over a two and a half year period, the NHGRI researchers identified 18 new genetic markers and generated a physical map for the large candidate region; collaboration with NCI and NIDDK enabled them to narrow the interval further. With the physical map in hand, collaborators at the University of Oklahoma were able to sequence the critical genomic region and all the genes were identified with help from bioinformatics experts Drs. Mark Boguski and Jane Weisemann in the NIH's National Center for Biotechnology Information. NHGRI and NIDDK researchers extracted full-length copies of most of those genes.

Dr. Marx and his colleagues led the effort to analyze DNA from individuals with MEN1 who came from 15 different families. The researchers applied a powerful method of searching for mutations called dideoxy fingerprinting. If no mutations were found, a candidate gene was excluded. After testing and excluding 10 genes the big break came. Out of 15 families, there were 12 different mutations, and the researchers knew this remarkable collaboration had come up with the right gene.

"The systematic and powerful process of positional cloning ultimately led the intramural NIH team to the identification of the MEN1 gene," says Dr. Chandrasekharappa, the paper's lead author.

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